The Notch pathway, as well as potential regulators or effectors HIFa/Notch signaling, have emerged as particularly relevant for establishing and maintaining heart function under hypoxic stress conditions. We generated/collected mutations of HIFa and Notch signaling in multiple cardiac compartments. We have gathered data suggesting that genetic ablation of Notch pathway activity in the mouse myocardium does not lead to cardiac remodeling in response to hypoxic conditions caused by myocardial infarction, but rather has a protective effect on cardiomyocytes after the infarct. Moreover, in the Drosophila heart model, an acute response to hypoxia (slowing of the heart rate) does not occur when Notch signaling is activated in the heart, and chronic hypoxia leads to a non-contractile, infarct-like condition of the heart. In contrast, HIF/Notch mutations in the mouse epicardium are deleterious to heart function, in that the response to transaortic constriction is aggravated and cardiac hypertrophy is increased. Thus, the epicardium plays also a critical role in the cardiac response to hypoxia. Thus, modulation of HIF as well as Notch signaling in various cardiac compartments is critical for the heart to respond and tolerate hypoxic conditions. We hypothesize that the interaction between HIF and Notch pathways are key to the regulation of the response to hypoxia, that HIF/Notch signaling elicits unique responses in the myocardium versus the epicardium, and that the HIF/Notch-dependent mechanisms protect cardiac function. In this proposal, we will study the respective contribution and interactions of HIF and Notch signaling to hypoxia tolerance and susceptibility in the heart. Based on the evolutionary conservation of the hypoxia response, mechanisms of cardiac hypoxia responses identified in the fly heart, involving HIF and Notch signaling, promise to be of relevance to the mammalian heart. Insights gained here are likely to lead to new avenues for finding treatments for hypoxia-induced cardiac injury.